Currently, the interleukin 17 (IL-17) family includes six cytokines, namely, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E and IL-17F. The members of the IL-17 family do not share sequence similarity with any other known cytokines, and also share relatively low sequence similarity among themselves (Gaffen S L, Nat. Rev. Immunol. 2009 August; 9(8):556-67). Function of the IL-17 family members is mainly involved in the modulation of the immune response.
IL-17A, a homodimer glycoprotein of 20-30 kD, is mainly produced by activated CD4+T cells, and acts as a pro-inflammatory cytokine. IL-17 is secreted by activated T cells at an inflammatory site, not during the systemic circulation. IL17 has many biological properties, including up-regulating adhesion molecules, and inducing the production of numerous inflammatory cytokines and chemokines in various cell types, including synovial cells, cartilage cells, fibroblasts, endothelial cells, epithelial cells, keratinocytes and macrophages. In addition, IL-17 induces the aggregation of neutrophilic granulocytes at an inflammation site by inducing the release of chemokines, stimulates the production of prostaglandins and metalloproteases, and inhibits the synthesis of proteoglycans. Moreover, IL-17 plays a critical role in the maturation of hemopoietic progenitor cells. IL-17 is involved in the signal transduction in various organs and tissues, including lung, articular cartilage, bone, brain, hemopoietic cells, kidneys, skin and intestines. Therefore, the immune reaction mediated by IL-17A/Th17 is systemic, and leads to an inflammatory reaction mainly expressed as neutrophilic granulocyte infiltration.
As demonstrated by extensive studies, the increase in IL-17 is involved in various diseases, including airway inflammation, rheumatoid arthritis (RA), osteoarthritis, bone erosion, inflammatory bowel disease (IBD), allograft rejection, psoriasis, some types of cancer, angiogenesis, atherosclerosis and multiple sclerosis (MS) (Witkowski et al., Cell. Mol. Life Sci. 61:567-579, 2004). Additionally, IL-17 plays a role in the degradation of collagen matrix, inflammation and joint injury, independent of IL-lb. Also, IL-17 and TNF-α synergistically increase inflammation. As confirmed by further studies, by blocking the in vivo biological activity of IL-17 with an antibody specifically binding to IL-17 or a soluble IL17 receptor, inflammation and bone erosion in various animal arthritis models are effectively reduced. Therefore, IL-17 becomes a new therapeutic target for RA and other autoimmune diseases. Moreover, since IL17 is mainly present in an inflammatory site, a medicament targeting IL17 may potentially have higher safety than medicaments targeting other pro-inflammatory cytokines in systemic circulation (e.g. TNF).
Currently, European Union and the FDA in the US have approved Cosentyx from Novartis Pharma AG for treating adult patients suffering from moderate-to-severe plaque psoriasis. The active ingredient of Cosentyxus is secukinumab, which is a monoclonal antibody against IL-17. Nevertheless, there is still a need in the art in more improved anti-IL-17 antibodies suitable for treatment of a patient.